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1 The Development oftheCoronary Arteries
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in favour of the formation of arterial endothelium
from ventricular endocardium. This concept proposed that the endocardial cells became trapped
during alleged coalescence of the ventricular trabeculations to form the compact parts of the ventricular walls [16]. Since there is no evidence that
the compact ventricular wall is formed by socalled “compaction”, this nal piece of evidence
must now be questioned. Intertrabecular spaces,
nonetheless, can become connected to the epicardial coronary arteries when the heart is congenitally malformed. There can be little question,
therefore, but that the endothelial linings of the
developing coronary arteries within the ventricular walls originate, at least in part, from epicardially derived cells. And, in abnormal situations,
endocardial channels from the ventricular cavities
can make direct connections with these mural
coronary arteries, and thence with the major epicardial coronary arteries.
In contrast to the debate regarding the origin
of the endothelial lining of the coronary arteries,
there is general agreement that the vascular
smooth muscle is largely produced by epicardially derived cells. Molecular biological studies,
nonetheless, have shown that not all the smooth
muscle cells within the arterial walls are labelled
by epicardially derived markers. Some of the
myocytes in the arterial walls are derived either
from the neural crest or from the second heart
eld [17, 18]. And signicantly, it is the initial
stems of the major coronary arteries as they originate from the valvar sinuses that have been shown
to have an endothelial lining of neural crest origin [19]. The brous components of the arterial
walls are almost certainly derived primarily from
the epicardium [20], although the possibility
remains that some broblasts could arise from
bone marrow cells [21]. Combining all this data
produces the notion that the coronary arterial network is a developmental mosaic [3]. In terms of
the understanding of malformed coronary arteries, nonetheless, the key features are the connection of the epicardial coronary arteries to the
aortic root, and the connection between the mural
arterial vasculature and the epicardial arteries
themselves. These processes, in turn, are intimately linked with the formation of the compact
components of the ventricular walls. It is an
understanding of these processes, therefore, that
is our primary focus.
Development oftheHuman Heart
In their review of normal and abnormal coronary
arteries [3], the Working Group of Developmental
Pathology emphasises that much of our knowledge of development is driven by experiments
made using the mouse. Evidence from murine
development now serves to conrm inferences
that can be made when with regard to the mechanism of connection of the epicardial coronary
arteries to the aortic root [8]. When seeking to
consider the relationship of developmental events
to congenital cardiac malformations, however, it
is important to concentrate on human cardiac
embryonic development. The major changes
span the fth through the eighth week subsequent
to fertilisation. These stages of development are
usually described using the system developed at
the Carnegie Institute, in the United States of
America [22]. The key stages are those extending
from 10 through 23. By Carnegie stage (CS) 13,
when the embryo is around 32days old, the initial heart tube has passed through the stage known
as looping. It is then possible to observe the apical components of the developing right and left
ventricles, which are forming from the inlet and
outlet parts of the ventricular loop. The developing atrial chambers at this stage open exclusively
into the developing left ventricle, with the developing right ventricle supporting the entirety of
the outow tract. The outow tract is serpentine.
Its walls, signicantly, are myocardial to its junction, at the margins of the pericardial cavity, with
the aortic sac (Fig.1.1). At this stage of development, the ventricular walls are formed mostly by
a meshwork of the trabeculations, with endocardium encircling each of the individual trabeculations. The compact layer of the ventricular walls
is barely formed.
By CS 15, when the embryo is around 36days
old, the atrioventricular canal has expanded such
that a direct connection is established between
the right ventricle and the right atrium. The out-
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a
c
Fig. 1.1 The panels show frontal sections taken from
three different human embryos at CS 13, which represents
around 32 days of development subsequent to fertilisation. Panel A shows the ventricular loop, with the developing right ventricle supporting the outow tract. Panel B is
a section through the outow tract, showing that its walls
b
are myocardial to the margins of the pericardial cavity
(white arrows with black borders). Panel C is a section
through the atrioventricular canal, which is supported
exclusively at this stage by the developing left ventricle.
Note that the ventricular walls are made up mostly of trabeculations, with a very thin compact layer
ab
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ow tract, nonetheless, remains supported exclusively by the developing right ventricle. A
signicant change has taken place, however, with
regard to the extent of its myocardial walls. The
entirety of the developing right ventricle, including the outow tract, is known to be formed by
migration of cells into the heart tube from the socalled second heart eld. Additional cells continue to populate the arterial pole of the tube
between CSs 13 and 15. Unlike the initial
migrations, the new cells are non-myocardial.
They form the intrapericardial components of the
arterial trunks [23]. At the same time, a protrusion extends from the dorsal wall of the aortic sac
into the cavity of the distal outow tract. This
separates the newly formed non-myocardial
component into the intrapericardial aorta and
pulmonary trunk. By CS 15, the protrusion has
fused with the distal margins of the mesenchymal
cushions that themselves fuse to separate the
remainder of the outow tract (Fig.1.2).
The cushions themselves are derived by a process of epithelial-to-mesenchymal transformation within the cardiac jelly that extends
throughout the outow tract. Concomitant with
the appearance of the non-myocardial walls to
form the distal part of the outow tract, the distal
margins of the cushions regress towards the base
of the developing right ventricle in parallel with
proximal regression of the distal myocardial border. At the same time, swellings are formed at the
proximal ends of the tongues of the nonmyocardial tissues that are forming the parietal
walls of the intrapericardial arterial trunks. These
swellings, identied by Kramer as the intercalated valvar swelling [24], interpose between the
parietal distal margins of the major cushions. In
this way, they permit the recognition of the primordiums of the developing arterial root within
the area that can now be nominated as the middle
part of the outow tract [23]. It is within this middle part that the distal outow cushions, along
Fig. 1.2 The images show sections from the same human
embryo at Carnegie stage (CS) 15, when the embryo is
around 36days old. Panel A is a section through the atrioventricular canal, which has expanded to provide the right
ventricle with its inlet component. The primary atrial septum is growing towards the canal, and will separate the
right and left atrial chambers. Note that the ventricular
walls continue to be formed primarily by a meshwork of
trabeculations, with a thin compact component. Panel B
shows the developing outow tract, which is being separated into the aortic and pulmonary channels. It now possesses three parts, with the middle part delineated by the
extent of the so-called intercalated valvar swellings,
which will form the non-adjacent leaets of the aortic and
pulmonary valves. In this image, only the pulmonary
swelling is shown. The distal myocardial border has now
regressed to the level of the junction between the distal
and middle parts of the outow tract
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a
Fig. 1.3 The images show frontal sections from the same
human embryo at Carnegie stage (CS) 17, when around
40days have passed subsequent to fertilisation. Panel A
shows the developing aortic root, which has been separated from the developing pulmonary root, which is shown
in Panel B.Both roots remain supported by the developing
right ventricle, and both are enclosed within the collar of
the middle myocardium. The protrusion from the dorsal
with the intercalated valvar swellings, remodel to
produce the leaets of the arterial valves. It is
within this middle myocardial collar, furthermore, that we see the initial formation of vascular
endothelial channels. Additional channels, nonetheless, form within the walls of the distal nonmyocardial outow tract. These distal vessels
have been dubbed the “peritruncal plexus” [7].
The crown-like plexus formed with the myocardial walls of the middle part of the outow tract
is discrete from the peritruncal plexus found
within the distal outow tract. Indeed, it is arguable that, so as to understand the relationships to
congenital malformations, it is the fate of this
middle part of the outow tract that is the key to
understanding.
The fusion of the protrusion formed from the
dorsal wall of the aortic sac with the distal margins of the outow cushions is the prelude to separation of the middle part of the outow tract into
the future aortic and pulmonary roots. This sepa-
b
wall of the aortic sac has fused with the distal margins of
the outow cushions, which themselves have fused in the
middle part of the outow tract. The cushions, however,
remain to fuse in the proximal outow tract. The ventricular walls remain formed predominantly by trabeculations,
with each trabeculation surrounded by its own endothelial
sleeve. As yet, it is not possible to recognise any epicardial
vascular channels
ration can be seen by CS 17, when the embryo has
passed through around 40days subsequent to fertilisation (Fig. 1.3). Subsequent to the fusion of
the protrusion from the dorsal wall of the aortic
sac with the distal margins of the outow cushions, the arterial roots are separated one from the
other, but as yet there has been no remodelling of
the distal margins of the cushions and the intercalated valvar swellings, which remain ush with
the distal myocardial border. And it is the myocardial border that marks the boundary between the
middle part of the outow tract and its distal nonmyocardial components. The ventricular walls at
this stage, furthermore, remain formed predominantly by the meshwork of trabeculations. As yet,
it is not possible to recognise any formation of
vascular channels within the epicardial covering
of the chambers, nor within the thin compact
components of the ventricular walls. It rst
becomes possible to recognise the beginning of
remodelling to produce arterial valvar leaets at
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a
Fig. 1.4 The images are sagittal sections through a
human embryo at Carnegie stage (CS) 19, when the
embryo is almost 7 weeks old. Panel A shows a cut
through the left side, showing the developing pulmonary
root. Panel B is a higher-powered image through the dorsally located aortic root. The root remains aligned with the
cavity of the right ventricle, but the proximal cushions by
now have fused with each other to build a shelf, which
connects the root with the cavity of the left ventricle. The
fused proximal cushions are now myocardialising, and
CS 19, when the embryo is almost 7weeks old.
Even at this stage, nonetheless, the middle part of
the outow tract remains encased almost exclusively within its myocardial collar (Fig.1.4). By
this stage, the proximal outow cushions have
themselves fused, thus building a shelf in the roof
of the right ventricle. This process creates a channel between the aortic root, which is still supported by the right ventricle, and the
interventricular communication. A channel still
persists, however, between the aortic root and the
cavity of the right ventricle. The closure of this
aorto-right ventricular channel, by tubercles
derived from the atrioventricular cushions, serves
to convert the interventricular foramen into the
outow tract for the left ventricle. The tubercles
then become the membranous part of the septum.
By this stage, the remodelling of the cushions and
the intercalated valvar swellings, producing the
b
will eventually largely form the infundibulum of the right
ventricle. The cushion shown in the image will fuse with
the tubercles of the atrioventricular cushions to close the
tertiary interventricular communication. The distal margins of the cushions are beginning to remodel to form the
leaets of the arterial valves, but remain encased in a collar of the middle outow tract myocardium. The ventricular walls, however, remain formed mostly by
trabeculations. There is still no evidence of the formation
of epicardial vascular channels
leaets of both arterial valves, is obvious
(Fig.1.4). Both arterial roots, nonetheless, remain
largely encased within the turret of the middle
outow tract myocardium. And the ventricular
walls remain largely trabeculated. Still there has
been no formation of any epicardial vascular
channels, nor arterial channels within the thin
compact ventricular walls.
Only during CSs 21 and 22, when the embryo
is at the beginning of the eighth week of development, does it become possible to recognise the
appearance of vascular channels. These are
formed initially in the developing atrioventricular
and interventricular grooves, but also in abundance within the myocardial walls that continue
to surround the middle part of the outow tract
(Fig. 1.5). The channels in the atrioventricular
and interventricular grooves will form the major
epicardial arteries. In addition to these endothe-
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ab
Fig. 1.5 The frontal sections are taken from a human
embryo at Carnegie stage (CS) 21, when the embryo is at
the beginning of the eighth week of development. It is at
this stage that it rst becomes possible to recognise the
endothelial channels that will become the coronary arteries. As shown in Panel A, the stem of the left coronary
artery is emerging from the intrapericardial aorta. It is distal to the boundary with the developing aortic root. As
shown in panel B, the tubercles of the atrioventricular
cushions have fused to close the persisting communica-
lial channels, an extensive circumferential plexus
can now be recognised within the myocardial
walls that continue to surround the middle part of
the outow tract. Although the distal cushions
and swellings have undergone additional remodelling as they form the valvar leaets, they still
remain supported, in their larger part, by the
myocardium of the middle part of the outow
tract. Signicantly, however, endothelial channels can now be seen growing out of the aortic
trunk just distal to the myocardial border. These
channels form the main stems of the coronary
arteries. The stem of the left coronary artery is
recognisable in the embryo shown in Fig.1.5. In
another embryo in the Human Developmental
Biology Resource (HDBR) archive, considered
to represent CS 22, it is possible to recognise the
stem of the right coronary artery. As with the
stem of the left coronary artery shown in
tion between the aortic root and the right ventricle, even
though the aortic root itself remains aligned with the cavity of the right ventricle. It is now possible to recognise
the endothelial channels that will become the major coronary arteries, along with an extensive plexus within the
myocardial walls that still enclose the middle part of the
outow tract. As yet, however, there has been minimal
formation of the arterial walls of the valvar sinuses. The
compact component of the ventricular walls, however, is
now beginning the thicken
Fig.1.5b, it arises from the intrapericardial aorta
distal to the border of the myocardium surrounding the middle part of the outow tract (Fig.1.6).
CS 23 marks the end of the embryonic period
of development, by which time the embryo is
8weeks old. By this stage, ongoing growth of the
non-myocardial tissues permits recognition of
the beginning of the formation of the arterial valvar sinuses. At CS 23, however, the stems of the
right and left coronary arteries remain at the level
of the sinutubular junction. They take a transmural course within the adventitial lining of the
developing sinuses merge before they merge with
the major coronary arteries, which by this stage
have developed from the circumferential plexus
initially formed within the myocardial walls of
the middle part of the outow tract. Although the
compact layer of the ventricular walls has begun
to thicken, the trabecular meshwork remains
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a
Fig. 1.6 The sections are taken through the developing
left ventricular outow tract of a human embryo at
Carnegie stage (CS) 22, in the eighth week of development. Panel A shows the vascular channels that form the
peritruncal plexus within the myocardial walls of the middle part of the outow tract. Note the ongoing remodelling
a
b
of the intercalated valvar swelling to form the nonadjacent leaet of the aortic valve. Panel B shows how the
stem of the right coronary artery is growing out of the
intrapericardial aorta just distal to the myocardial border.
It is extending to join with the endothelial channels of the
peritruncal plexus
b
Fig. 1.7 The sections are taken from a human embryo at
Carnegie stage 23, which is at the end of the eighth week
of development. Panel A shows an oblique cut through the
right ventricle, the aortic root, and the pulmonary trunk.
The stem of the left coronary artery can be seen taking an
prominent. Although the major epicardial coronary arteries are recognisable within the atrioventricular and interventricular grooves in the
particular embryo representing CS 23 in the
intramural course through the adventitial lining of the
developing left coronary arterial sinus. Panel B is a magnied view taken from the next serial section to the right.
It shows that the opening of the artery, at this stage, is at
the level of the developing sinutubular junction
HDBR archive, there is still no evidence of the
formation of arterial channels within the developing compact ventricular walls (Fig.1.7). Although
it was not possible to identify endothelial chan-
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Fig. 1.8 The image shows the short axis of the left ventricle in a human embryo graded at Carnegie stage 22,
which is in the eighth week of development. In this
embryo, it is possible to recognise developing endothelial
channels in both the interventricular grooves and the compact walls. The trabeculations are diminishing in their
thickness, while the compact wall is thickening
nels within the walls of the embryo shown in
Fig.1.7, which had been graded as CS 23, it was
possible to identify the channels in another
human embryo retained in the Hamilton archive.
This embryo had been considered to represent
stage 22 (Fig.1.8). The mural channels had only
an endothelial wall. The vessels developing
within the interventricular grooves, in contrast,
were duplicated. One of the channels in both
grooves, furthermore, was developing a smooth
muscular component as part of its walls.
Evidence fromMurine Development
At the moment, our access to human embryos is
limited by the number of datasets available in the
Human Developmental Biology Resource. Other
datasets are in the process of preparation, and we
anticipate being able to generate further information regarding the fate of the vascular channels
seen already at CS 22. In this regard, we will further be able to assess the formation of the valvar
R. H. Anderson et al.
sinuses as we prepare material from the early
weeks of the foetal period of development. We
are able, nonetheless, already to support our concept of development on the basis of the availability of a large number of murine embryos and
foetuses prepared using the technique of episcopic microscopy. In the mouse heart, the intrapericardial aorta becomes separated from the
pulmonary trunk within the distal outow tract at
embryonic day 12.5. Embryonic day 13.5in the
mouse is the stage of beginning of closure of the
embryonic interventricular communication, and
hence comparable to CS 21 in humans. It is at
this stage in the mouse that it becomes possible to
identify the outgrowth of buds from the intrapericardial aortic trunk. As in humans, the buds originate distal to the boundary between the distal and
middle parts of the outow tract (Fig.1.9).
By embryonic day 14.5, which is the day on
which the interventricular communication is
closed in the mouse, the orices of the coronary
arteries are evident in all embryos. The orice of
the right coronary artery, however, remains distal
to the developing sinutubular junction, while the
orice of the left coronary artery is typically
found at the level of the junction (Fig.1.10).
With ongoing development during the foetal
period, there is further regression of the distal
border of the myocardium covering the middle
part of the outow tract, with this regression
accompanied by further development of the arterial valvar sinuses. And, concomitant with the
growth of the sinuses, the orices of the coronary
arteries are translocated so that, by embryonic
day 15.5, they take their origin within the sinuses,
proximal to the sinutubular junction (Fig.1.11).
At the same time, as was the case in the human
heart, there is thickening of the compact components of the ventricular walls, accompanied by
reciprocal diminution in thickness of the trabeculations. The trabeculations do coalesce to form
the papillary muscles of the developing atrioventricular valves (Fig.1.12). In the right ventricle,
the trabeculations also coalesce to form the septomarginal and septoparietal trabeculations, with
one trabeculation becoming prominent as the
moderator band.
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a
Fig. 1.9 The images are taken from the same threedimensional dataset prepared from a mouse embryo at
embryonic day 13.5. Panel A shows the origin of the bud
of the right coronary artery distal to the boundary between
the distal and middle parts of the outow tract. Panel B
shows the bud of the left coronary artery, again originating
b
distal to the myocardial border, which is shown by the
white arrows with black borders. The section showing the
left coronary artery, however, has been taken to show its
connection with the arteries developing from the peritruncal plexus within the myocardial wall of the middle part of
the outow tract
a
Fig. 1.10 The images are taken from a three-dimensional
dataset prepared from a mouse embryo at embryonic day
14.5. Panel A shows how, at this stage, the orice of the
right coronary artery remains distal to the developing
sinutubular junction. The left coronary artery, as shown in
b
panel B, connects with the aortic root at the level of the
sinutubular junction, with the epicardial component of the
artery within the myocardial wall of the middle part of the
outow tract
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a
Fig. 1.11 The images are from a dataset prepared from a
mouse foetus at embryonic day 15.5. Both coronary arteries have now been remodelled so as to arise within the
valvar sinuses proximal to the sinutubular junction. These
a
Fig. 1.12 The images are four chamber sections through
the ventricular mass of mouse foetuses at embryonic day
15.5 (panel A) and 18.5 (panel B). They show how, subsequent to closure of the embryonic interventricular communication at embryonic day 14.5, there is ongoing
b
images show the origin of the right coronary artery, seen
from the aspect of the right coronary aortic sinus in panel
(a), and in cross-section in panel (b)
b
thickening of the compact layer of the ventricular walls,
with diminution in the part made of trabeculations. The
trabeculations themselves, whilst not coalescing to form
the compact wall, do come together to form the papillary
muscles of the atrioventricular valves
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